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dc.contributor.authorFabre, Margarete A
dc.contributor.authorde Almeida, José Guilherme
dc.contributor.authorFiorillo, Edoardo
dc.contributor.authorMitchell, Emily
dc.contributor.authorDamaskou, Aristi
dc.contributor.authorRak, Justyna
dc.contributor.authorOrrù, Valeria
dc.contributor.authorMarongiu, Michele
dc.contributor.authorChapman, Michael Spencer
dc.contributor.authorVijayabaskar, MS
dc.contributor.authorBaxter, Joanna
dc.contributor.authorHardy, Claire
dc.contributor.authorAbascal, Federico
dc.contributor.authorWilliams, Nicholas
dc.contributor.authorNangalia, Jyoti
dc.contributor.authorMartincorena, Iñigo
dc.contributor.authorCampbell, Peter J
dc.contributor.authorMcKinney, Eoin F
dc.contributor.authorCucca, Francesco
dc.contributor.authorGerstung, Moritz
dc.contributor.authorVassiliou, George S
dc.date.accessioned2022-07-03T01:02:45Z
dc.date.available2022-07-03T01:02:45Z
dc.date.issued2022-06
dc.identifier.issn0028-0836
dc.identifier.otherPMC9177423
dc.identifier.other35650444
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/338718
dc.descriptionFunder: European Research Council
dc.description.abstractClonal expansions driven by somatic mutations become pervasive across human tissues with age, including in the haematopoietic system, where the phenomenon is termed clonal haematopoiesis1-4. The understanding of how and when clonal haematopoiesis develops, the factors that govern its behaviour, how it interacts with ageing and how these variables relate to malignant progression remains limited5,6. Here we track 697 clonal haematopoiesis clones from 385 individuals 55 years of age or older over a median of 13 years. We find that 92.4% of clones expanded at a stable exponential rate over the study period, with different mutations driving substantially different growth rates, ranging from 5% (DNMT3A and TP53) to more than 50% per year (SRSF2P95H). Growth rates of clones with the same mutation differed by approximately ±5% per year, proportionately affecting slow drivers more substantially. By combining our time-series data with phylogenetic analysis of 1,731 whole-genome sequences of haematopoietic colonies from 7 individuals from an older age group, we reveal distinct patterns of lifelong clonal behaviour. DNMT3A-mutant clones preferentially expanded early in life and displayed slower growth in old age, in the context of an increasingly competitive oligoclonal landscape. By contrast, splicing gene mutations drove expansion only later in life, whereas TET2-mutant clones emerged across all ages. Finally, we show that mutations driving faster clonal growth carry a higher risk of malignant progression. Our findings characterize the lifelong natural history of clonal haematopoiesis and give fundamental insights into the interactions between somatic mutation, ageing and clonal selection.
dc.languageeng
dc.publisherSpringer Science and Business Media LLC
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.sourceessn: 1476-4687
dc.sourcenlmid: 0410462
dc.subjectClone Cells
dc.subjectHumans
dc.subjectLongitudinal Studies
dc.subjectPhylogeny
dc.subjectAging
dc.subjectMutation
dc.subjectGenome, Human
dc.subjectAged
dc.subjectMiddle Aged
dc.subjectClonal Hematopoiesis
dc.titleThe longitudinal dynamics and natural history of clonal haematopoiesis.
dc.typeArticle
dc.date.updated2022-07-03T01:02:44Z
prism.endingPage342
prism.issueIdentifier7913
prism.publicationNameNature
prism.startingPage335
prism.volume606
dc.identifier.doi10.17863/CAM.86131
dcterms.dateAccepted2022-04-19
rioxxterms.versionofrecord10.1038/s41586-022-04785-z
rioxxterms.versionVoR
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0/
dc.contributor.orcidOrrù, Valeria [0000-0002-6047-4625]
dc.contributor.orcidMarongiu, Michele [0000-0002-7289-9815]
dc.contributor.orcidChapman, Michael Spencer [0000-0002-5320-8193]
dc.contributor.orcidAbascal, Federico [0000-0002-6201-1587]
dc.contributor.orcidWilliams, Nicholas [0000-0003-3989-9167]
dc.contributor.orcidNangalia, Jyoti [0000-0001-7122-4608]
dc.contributor.orcidMartincorena, Iñigo [0000-0003-1122-4416]
dc.contributor.orcidCampbell, Peter J [0000-0002-3921-0510]
dc.contributor.orcidGerstung, Moritz [0000-0001-6709-963X]
dc.contributor.orcidVassiliou, George S [0000-0003-4337-8022]
dc.identifier.eissn1476-4687
pubs.funder-project-idWellcome Trust (104064/Z/14/Z)
pubs.funder-project-idEuropean Commission Horizon 2020 (H2020) Societal Challenges (633964)
pubs.funder-project-idCancer Research UK (23015)
pubs.funder-project-idLeukemia & Lymphoma Society (RTF6006-19)
cam.issuedOnline2022-06


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International